Skip to main content
PMC home page
Antimicrobial Agents and Chemotherapy logoLink to Antimicrobial Agents and Chemotherapy
. 1991 Jun;35(6):1254–1257. doi: 10.1128/aac.35.6.1254

Comparative inhibition of hepatitis B virus DNA polymerase and cellular DNA polymerases by triphosphates of sugar-modified 5-methyldeoxycytidines and of other nucleoside analogs.

E Matthes 1, K Reimer 1, M von Janta-Lipinski 1, H Meisel 1, C Lehmann 1
PMCID: PMC284326  PMID: 1929276

Abstract

Of a series of 14 nucleoside 5'-triphosphates, those of 2',3'-dideoxy-3'-fluoro-5-methylcytidine, 3'-azido-2',3'-dideoxy-5-methylcytidine, 2',3'-dideoxy-3'-fluoroguanosine, 2',3'-didehydro-2',3'-dideoxy-5-methylcytidine, 2',3'-dideoxy-3'-fluoro-5-ethylcytidine, and 2',3'-dideoxy-3'-fluoroadenosine emerged as the most potent inhibitors of hepatitis B virus DNA polymerase (50% inhibitory dose, 0.03 to 0.35 microM). In contrast, cellular DNA polymerases proved to be resistant to (alpha) or partially affected by (beta) these analogs. These compounds are among the most effective and selective inhibitors of endogenous hepatitis B virus DNA polymerase recognized to date.

Full text

PDF

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Cheng Y. C., Dutschman G. E., Bastow K. F., Sarngadharan M. G., Ting R. Y. Human immunodeficiency virus reverse transcriptase. General properties and its interactions with nucleoside triphosphate analogs. J Biol Chem. 1987 Feb 15;262(5):2187–2189. [PubMed] [Google Scholar]
  2. Chidgeavadze Z. G., Scamrov A. V., Beabealashvilli R. S., Kvasyuk E. I., Zaitseva G. V., Mikhailopulo I. A., Kowollik G., Langen P. 3'-Fluoro-2',3'-dideoxyribonucleoside 5'-triphosphates: terminators of DNA synthesis. FEBS Lett. 1985 Apr 22;183(2):275–278. doi: 10.1016/0014-5793(85)80792-4. [DOI] [PubMed] [Google Scholar]
  3. Civitico G., Wang Y. Y., Luscombe C., Bishop N., Tachedjian G., Gust I., Locarnini S. Antiviral strategies in chronic hepatitis B virus infection: II. Inhibition of duck hepatitis B virus in vitro using conventional antiviral agents and supercoiled-DNA active compounds. J Med Virol. 1990 Jun;31(2):90–97. doi: 10.1002/jmv.1890310205. [DOI] [PubMed] [Google Scholar]
  4. Farraye F. A., Mamish D. M., Zeldis J. B. Preliminary evidence that azidothymidine does not affect hepatitis B virus replication in acquired immunodeficiency syndrome (AIDS) patients. J Med Virol. 1989 Dec;29(4):266–267. doi: 10.1002/jmv.1890290409. [DOI] [PubMed] [Google Scholar]
  5. Fourel I., Hantz O., Watanabe K. A., Jacquet C., Chomel B., Fox J. J., Trepo C. Inhibitory effects of 2'-fluorinated arabinosyl-pyrimidine nucleosides on woodchuck hepatitis virus replication in chronically infected woodchucks. Antimicrob Agents Chemother. 1990 Mar;34(3):473–475. doi: 10.1128/aac.34.3.473. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Furman P. A., Fyfe J. A., St Clair M. H., Weinhold K., Rideout J. L., Freeman G. A., Lehrman S. N., Bolognesi D. P., Broder S., Mitsuya H. Phosphorylation of 3'-azido-3'-deoxythymidine and selective interaction of the 5'-triphosphate with human immunodeficiency virus reverse transcriptase. Proc Natl Acad Sci U S A. 1986 Nov;83(21):8333–8337. doi: 10.1073/pnas.83.21.8333. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. HOARD D. E., OTT D. G. CONVERSION OF MONO- AND OLIGODEOXYRIBONUCLEOTIDES TO 5-TRIPHOSPHATES. J Am Chem Soc. 1965 Apr 20;87:1785–1788. doi: 10.1021/ja01086a031. [DOI] [PubMed] [Google Scholar]
  8. Hantz O., Allaudeen H. S., Ooka T., De Clercq E., Trepo C. Inhibition of human and woodchuck hepatitis virus DNA polymerase by the triphosphates of acyclovir, 1-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)-5-iodocytosine and E-5-(2-bromovinyl)-2'-deoxyuridine. Antiviral Res. 1984 Aug;4(4):187–199. doi: 10.1016/0166-3542(84)90017-2. [DOI] [PubMed] [Google Scholar]
  9. Hao Z., Cooney D. A., Hartman N. R., Perno C. F., Fridland A., DeVico A. L., Sarngadharan M. G., Broder S., Johns D. G. Factors determining the activity of 2',3'-dideoxynucleosides in suppressing human immunodeficiency virus in vitro. Mol Pharmacol. 1988 Oct;34(4):431–435. [PubMed] [Google Scholar]
  10. Haritani H., Uchida T., Okuda Y., Shikata T. Effect of 3'-azido-3'-deoxythymidine on replication of duck hepatitis B virus in vivo and in vitro. J Med Virol. 1989 Dec;29(4):244–248. doi: 10.1002/jmv.1890290405. [DOI] [PubMed] [Google Scholar]
  11. Kassianides C., Hoofnagle J. H., Miller R. H., Doo E., Ford H., Broder S., Mitsuya H. Inhibition of duck hepatitis B virus replication by 2',3'-dideoxycytidine. A potent inhibitor of reverse transcriptase. Gastroenterology. 1989 Nov;97(5):1275–1280. doi: 10.1016/0016-5085(89)91699-5. [DOI] [PubMed] [Google Scholar]
  12. Lee B., Luo W. X., Suzuki S., Robins M. J., Tyrrell D. L. In vitro and in vivo comparison of the abilities of purine and pyrimidine 2',3'-dideoxynucleosides to inhibit duck hepadnavirus. Antimicrob Agents Chemother. 1989 Mar;33(3):336–339. doi: 10.1128/aac.33.3.336. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Löfgren B., Nordenfelt E., Oberg B. Inhibition of RNA- and DNA-dependent duck hepatitis B virus DNA polymerase activity by nucleoside and pyrophosphate analogs. Antiviral Res. 1989 Dec;12(5-6):301–310. doi: 10.1016/0166-3542(89)90057-0. [DOI] [PubMed] [Google Scholar]
  14. Matthes E., Langen P., von Janta-Lipinski M., Will H., Schröder H. C., Merz H., Weiler B. E., Müller W. E. Potent inhibition of hepatitis B virus production in vitro by modified pyrimidine nucleosides. Antimicrob Agents Chemother. 1990 Oct;34(10):1986–1990. doi: 10.1128/aac.34.10.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Matthes E., Lehmann C., Scholz D., Rosenthal H. A., Langen P. Phosphorylation, anti-HIV activity and cytotoxicity of 3'-fluorothymidine. Biochem Biophys Res Commun. 1988 Jun 16;153(2):825–831. doi: 10.1016/s0006-291x(88)81170-7. [DOI] [PubMed] [Google Scholar]
  16. Matthes E., Lehmann C., Scholz D., von Janta-Lipinski M., Gaertner K., Rosenthal H. A., Langen P. Inhibition of HIV-associated reverse transcriptase by sugar-modified derivatives of thymidine 5'-triphosphate in comparison to cellular DNA polymerases alpha and beta. Biochem Biophys Res Commun. 1987 Oct 14;148(1):78–85. doi: 10.1016/0006-291x(87)91078-3. [DOI] [PubMed] [Google Scholar]
  17. Matthes E., Lehmann C., von Janta-Lipinski M., Scholz D. Inhibition of HIV-replication by 3'-fluoro-modified nucleosides with low cytotoxicity. Biochem Biophys Res Commun. 1989 Nov 30;165(1):488–495. doi: 10.1016/0006-291x(89)91096-6. [DOI] [PubMed] [Google Scholar]
  18. Meisel H., Reimer K., von Janta-Lipinski M., Bärwolff D., Matthes E. Inhibition of hepatitis B virus DNA polymerase by 3'-fluorothymidine triphosphate and other modified nucleoside triphosphate analogs. J Med Virol. 1990 Feb;30(2):137–141. doi: 10.1002/jmv.1890300211. [DOI] [PubMed] [Google Scholar]
  19. Nordenfelt E., Löfgren B., Chattopadhyaya J., Oberg B. Inhibition of hepatitis B virus DNA polymerase by 3'-azido-3'-deoxythymidine triphosphate but not by its threo analog. J Med Virol. 1987 Jul;22(3):231–236. doi: 10.1002/jmv.1890220306. [DOI] [PubMed] [Google Scholar]
  20. Price P. M., Banerjee R., Acs G. Inhibition of the replication of hepatitis B virus by the carbocyclic analogue of 2'-deoxyguanosine. Proc Natl Acad Sci U S A. 1989 Nov;86(21):8541–8544. doi: 10.1073/pnas.86.21.8541. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Summers J., Mason W. S. Replication of the genome of a hepatitis B--like virus by reverse transcription of an RNA intermediate. Cell. 1982 Jun;29(2):403–415. doi: 10.1016/0092-8674(82)90157-x. [DOI] [PubMed] [Google Scholar]
  22. Tao P. Z., Johansson N. G., Stening G., Oberg B., Datema R. Inhibition of HIV-1 reverse transcriptase by 5'-triphosphates of 5-substituted uridine analogs. Antiviral Res. 1989 Dec;12(5-6):269–278. doi: 10.1016/0166-3542(89)90054-5. [DOI] [PubMed] [Google Scholar]
  23. Tao P. Z., Löfgren B., Lake-Bakaar D., Johansson N. G., Datema R., Oberg B. Inhibition of human hepatitis B virus DNA polymerase and duck hepatitis B virus DNA polymerase by triphosphates of thymidine analogs and pharmacokinetic properties of the corresponding nucleosides. J Med Virol. 1988 Dec;26(4):353–362. doi: 10.1002/jmv.1890260403. [DOI] [PubMed] [Google Scholar]
  24. Ueda K., Tsurimoto T., Nagahata T., Chisaka O., Matsubara K. An in vitro system for screening anti-hepatitis B virus drugs. Virology. 1989 Mar;169(1):213–216. doi: 10.1016/0042-6822(89)90057-3. [DOI] [PubMed] [Google Scholar]
  25. Waqar M. A., Evans M. J., Manly K. F., Hughes R. G., Huberman J. A. Effects of 2',3'-dideoxynucleosides on mammalian cells and viruses. J Cell Physiol. 1984 Nov;121(2):402–408. doi: 10.1002/jcp.1041210218. [DOI] [PubMed] [Google Scholar]

Articles from Antimicrobial Agents and Chemotherapy are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES